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236 Rational Approach for HVTN Phase I/II HIV Vaccine Trials
A. J. Rossini, S. G. Self*, M. Hudgens, and P. Gilbert
Fred Hutchinson Cancer Res. Ctr., Seattle, WA, USA
Background: The number of new vaccine candidates that will enter the HVTN for clinical evaluation over the next 12 to 18 months will be substantially greater than have previously been available at any time in the history of AVEG or HVTN. This increase, due primarily to the pump-priming efforts of the NIH, poses a significant challenge to the HVTN. To meet this challenge of efficiently conducting Phase I and II evaluations to rapidly (dis)qualify candidate regimens for efficacy trials, the HVTN will need to take a more focused and standardized approach to the evaluation process.
Methods: A 3-trial schema is proposed. The first is a standard dose-escalation safety study of a single vaccine regimen, with n = 10(15 per arm. The second trial is a novel selection design trial that considers the selection of the regimen with the "best" immunological response; for this trial, n = 20(40 per arm. The result of this trial is to pick only the best 1 or 2 arms for promotion to a Phase II characterization study. The third trial is a Phase II study (n = 60(120 per arm) to characterize and compare regimens with respect to qualification for Phase III efficacy trials. The proposed approach is evaluated and described through power calculations for various past and potential trial scenarios.
Results: This proposed schema shortens the decision-making time as well as the number of trials needed to justify promotion of a vaccine to a Phase III efficacy study. The use of the selection designs to promote 1 or 2 vaccine regimens requires additional scientific consideration of which factors are critical for the vaccine regimen (dose, schedule, delivery, and adjuvant), but provides a statistically sound method for decision making with a smaller sample size than would be needed using traditional designs.
Conclusions: This schema is being adopted as the standard approach for vaccine evaluation by the HVTN. By focusing on issues critical to deciding if a vaccine qualifies for a Phase III efficacy trial, it provides a rational evaluation strategy requiring fewer subjects as well as fewer trials. This is important for decreasing the time to efficacy evaluation for HIV vaccines.
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